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CLINICAL OVERVIEW

Persistent Depressive Disorder (Dysthymia)

Copyright © 2022 by Elsevier, Inc. All rights reserved.

Created 25 Agustus 2021.

Basic Information

Definition
• Persistent depressive disorder (dysthymia) is a mood disorder. Mood is a subjective
emotional state. It is normal human experience to have fluctuations in mood in
response to occurrences in everyday life. A change in mood becomes a “mood
disorder” when it significantly impairs functioning. Both the Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the ICD-10-CM
classify mood disorders into similar types. These include major depressive disorders
(unipolar, single episodes, and recurrent), persistent depressive disorder (dysthymia),
bipolar I disorder, bipolar II disorder, cyclothymic disorder, and mood disorder due
to medical conditions, substance-induced mood disorders, and the “unspecified”
unipolar and bipolar disorders.

• The DSM-5 consolidated chronic major depressive disorder (MDD) and dysthymic
disorder into persistent depressive disorder. For the diagnosis of persistent
depressive disorder (diagnosis code 300.40), DSM-5 specifies a chronic state of
depression for more than 2 yr. To qualify, the patient must have depressed mood for
most of the day, on more days than not, and have two or more of the following six

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symptoms: (1) poor appetite or overeating; (2) insomnia or hypersomnia; (3) low
energy or fatigue; (4) low self-esteem; (5) poor concentration or difficulty making
decisions; and (6) feelings of hopelessness.

Epidemiology & Demographics

The World Health Organization (WHO) ranks major depressive disorder as one of the
most prevalent and disabling diseases in the world. The 12-mo prevalence for major
depressive disorder is 5%, and the lifetime prevalence is 13%. Persistent forms of
depression represent a substantial proportion of depressive disorders, with a lifetime
prevalence ranging from 3% to 6% in the Western world. Patients with major
depressive disorder frequently have other comorbid mental health issues, including
anxiety disorders, personality disorders, and substance use disorders. 1

Pathophysiology 2
• A heterogeneous group of disorders probably arising from various etiologies.

• Genetic and environmental experiences, and their interaction, each contribute.

• Significant psychosocial stressors, including loss and history of childhood abuse or

adversity, often trigger depression, particularly for first episodes.

• Numerous biologic correlates have been identified, though none is considered

causative or diagnostic. Genes that influence the production and reuptake of
serotonin, norepinephrine, dopamine, and glutamate, as well as nerve cell growth in
brain regions underlying memory and emotional processing, are of greatest interest.
Abnormalities in brain regions underlying executive functioning, emotion
regulation, and reward processing, as well as irregularities in functional connectivity
have been identified. Irregularities in cortisol responding and inflammation also
may play a role.

• Cognitive risk factors include a pessimistic style of explaining negative events, a

tendency to ruminate, and biases in processing emotional information and events.

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Clinical Manifestations

Presenting Signs & Symptoms

• Physical symptoms may include the following:

1. Tiredness or low energy

2. Eating or sleeping too much or too little

3. Being restless or agitated

4. Unexplained physical complaints

• Mental and emotional symptoms may include the following:

1. Feeling hopeless, worthless, or guilty

2. Anxiety

3. Trouble focusing or making decisions

4. Low self-esteem

5. Negative outlook

6. Feeling irritable

7. Being unable to have fun or feel pleasure

• Behavioral symptoms may include the following:

1. Withdrawing from others

2. Aggressive behavior or anger

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Diagnosis
• History and physical examination should focus on determining if the patient has a
mood disorder or the possibility that drug abuse, medications, or a general medical
condition may be responsible for the patient’s condition instead. Many patients and
families are reluctant to acknowledge depression because of stigma. It is essential to
identify medical conditions that may exacerbate a psychiatric presentation.

• The psychiatric history should ask about current symptoms, precipitating events
(e.g., job loss or relationship), past psychiatric and substance history, history of self-
harm or suicide attempts, and identification of support systems.

• A two-question screener is as effective as longer instruments. A positive answer to

either question warrants a full assessment.

1. Over the past 2 weeks, have you ever felt down, depressed, or hopeless?

2. Over the past 2 weeks, have you felt little interest or pleasure in doing things?

• Even if not suggested by the patient, careful questioning of suicidal thoughts is

necessary. All threats of suicide should be taken very seriously. Clinicians can use the
mnemonic SAL: Is the method specific? Is it available? Is it lethal?

• A tentative diagnosis can be established by use of DSM-5 criteria. Laboratory tests to

investigate medical conditions may be necessary based on the specifics of the clinical
presentation, but no tests can confirm or exclude mood disorders. 1

Laboratory Tests
• Laboratory evaluation is generally not helpful. Research is underway to identify
biomarkers that may be useful in diagnosis, but as of yet no laboratory studies are
diagnostic.

• The following can assist in ruling out other confounding issues:

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1. Routine blood chemistry evaluation

2. CBC with differential

3. Thyroid function studies

4. Vitamin B12 levels

Differential Diagnosis 1
The differential diagnosis of persistent depressive disorder is outlined below.
Guidelines to differential diagnosis are summarized in Table E1.

TABLE E1
Guidelines to the Differential Diagnoses
From Novac A: Depressive, bipolar, and related mood disorders. In Kellerman RD, Rakel DP: Conn’s current therapy,
Philadelphia, 2021, Elsevier, pp 795–806.

Diagnosis Similarities Differentiating Clinical Clues Treatment Response

Details

Major Depressed MDD: Acute or MDD: Usually a MDD: Antidepressants and/or

depression mood; subacute onset; marked drop in initial antianxiety medications;
(MDD) depressive possible recent functionality consider psychotherapy
versus cognition life stressors; PDD: Significant PDD: Cognitive-behavioral
persistent (pessimism); and often more chronic impairment; psychotherapy; antidepressants
depressive and numerous often symptoms are (often long term); sometimes
disorder vegetative symptoms egosyntonic; and enhancement pharmacology
(dysthymia) symptoms PDD: May “personality
(PDD) (physical) overlap with disorder” flavor
MDD; chronic,
fluctuating
course

Mixed mania Psychomotor Mixed mania: Mixed mania: Mixed mania: Mood stabilizers;
versus agitation; Labile affect; Personal and family caution regarding antidepressants:
agitated dysphoria; often rapid history can cause worsening
depression and mood switch with brief
swings euphoric states

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Agitated Agitated depression: Agitated depression:

depression: No Anxiety symptoms, Antidepressants and sedating
euphoric states; often subtle, precede mood stabilizers; avoid long-term
severe anxiety, depressive symptoms tranquilizers
including
sympathetic
symptoms

Mania Intermittent Mania: Distinct Mania: More often Mania: Mood stabilizers; caution
versus states of states of high severe insomnia about antidepressants; and
cyclothymia high energy energy; without fatigue; atypical antipsychotics if needed
and depression is severity of mania and
euphoria sometimes insomnia directly
with or unnoticed related
without
recurrent
depression

Cyclothymia: Cyclothymia: May Cyclothymia: Same as above,

Distinct cycling take unpredictable according to clinical judgment
from depression forms; fluctuation of
to hypomania mood and sleep

Substance Intermittent Substance Substance abuse: Substance abuse: Rehabilitation;

abuse use of abuse: Look for specific treat underlying psychiatric
disorder stimulant Substance abuse syndromes; drug symptoms
versus abuse may tends to escalate screen
cyclothymia mimic
cycling
mood
disorder;
may coexist

Cyclothymia: Cyclothymia: Cyclothymia: Mood stabilizers

Cyclothymia Negative drug and/or antidepressants and/or
may remain screens; no atypical antipsychotics
constant for withdrawals; and no
years (even drug culture history
lifelong)

Personality More often Personality Personality disorder: Personality disorder: Acute

disorder overlap; disorder: Long- Borderline decompensation; long-term
versus mood requires term pervasive personality disorder psychotherapy; mood stabilizers;
disorder concomitant history since includes mood and atypical antipsychotics
treatment adolescence lability/depressive
episodes; often
narcissistic
personality includes
grandiose/hypomanic
states

Mood disorder: Mood disorder: More Mood disorder: See treatment of

More often often symptoms are mood disorders
episodic egodystonic

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Bereavement May overlap; Bereavement: Bereavement: Bereavement: Social support; grief

versus MDD attention to Tends to Preoccupation with counseling; psychotherapy; and if
recent major improve over loss persists MDD present, treat as MDD
loss; time
sometimes
similar
picture;
bereavement
and MDD
may co-
occur

MDD: Tends to MDD: Duration of MDD: See treatment of MDD

worsen over average major
time depressive episode is
9 mo

Terminal May overlap; MDD has better Fear of and Both warrant trial with
illness– attention to response to preoccupation with antidepressants, recommended
related symptom medications death often progress before any end-of-life decisions
mood patterns with progression of
(TIRM) medical condition
changes
versus MDD

TIRM Experimental only: Treatment with

dominated by entheogen-enhanced
sadness and psychotherapy (psilocybin, lysergic
grief acid diethylamide [LSD],
methylenedioxymethamphetamine
[MDMA]) ∗

Primary Clinical Primary mood Neurologic, Treat both primary medical

mood picture may disorder: May endocrine, infectious, condition and mood disorder;
disorder be identical be triggered by systemic, and blood treatment same as for primary
versus mood external disorders mood disorder
disorder stressful events
arising from
medical
condition

Medical
condition: Often
onset is
insidious;
sometimes
precedes
medical
condition

∗ Not yet approved for use in the United States.

I. Medical Disorders, Medications, and Substance Abuse or Withdrawal:

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Medical disorders, medications, and substance abuse or withdrawal can either cause or
mimic mood disorders. The patient with symptoms and signs of depression may have
an unrecognized malignant neoplasm or sedative intoxication. Differential diagnostic
considerations for manic symptoms include stimulant abuse (e.g., cocaine,
amphetamines), hallucinogen abuse, alcohol or sedative withdrawal, delirium,
hyperthyroidism, and other medical conditions causing agitation. See the previous
section for further information. Patients may be treated with antidepressant
medication for a variety of disorders other than depression, such as anxiety, obsessive-
compulsive disorder, posttraumatic stress disorder, pain syndromes, smoking
cessation, and vasodepressor syncope.

II. Grief and Bereavement:

Grief and bereavement are normal human reactions to the acute loss of another person,
health, social position, or job. The period of mourning is characterized by sadness,
diminished sense of well-being (somatic complaints), sleeplessness, and sadness
triggered by thoughts of the loss. Normal grief, however, does not include guilt, loss of
self-esteem, feelings of worthlessness, suicidal intent, psychomotor retardation, or
occupational dysfunction. The duration of normal grief and bereavement differs
among cultures and among individuals within cultures, but severe symptoms normally
resolve within 6 to 12 mo.

III. Adjustment Disorders:

Adjustment disorders are behavioral or emotional disorders that occur in response to

an identifiable stress or stressors, with marked distress that is out of proportion to the
severity of the stressor. The emotional component can involve sadness, low self-esteem,
suicidal behavior, hopelessness, helplessness, or other self-threatening behavior. Acute
adjustment disorder occurs within 3 mo of the stressor and does not last longerthan 6
mo. The stressors are typically not as severe as those precipitating bereavement
reaction, and the responses are often more maladaptive.

IV. Borderline Personality Disorder:

Borderline personality disorder is characterized by unstable personal relationships,

unstable self-image, and self-destructive behaviors. The disorder may include chronic
feelings of emptiness, which may be misdiagnosed as depression, or reactivity of mood,
which may be mistaken for mania or hypomania. These patients typically live lives of
crisis and constant conflict.

V. Dementia:

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Dementia can be confused with depression but is characterized by abnormal mental

status, including abnormalities in tests of memory, calculation, and judgment.

Treatment 2
• Good evidence that cognitive-behavioral therapy is as effective as antidepressant
medication in achieving significant reduction or remission 3 (Table E2).

TABLE E2
Treatments of Depression
From Goldman L et al: Goldman ’ s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

Name of Approach
Psychotherapy

Cognitive Identify and correct negativistic patterns of thinking.

psychotherapy

Interpersonal Identify and work through role transitions or interpersonal losses, conflicts,
psychotherapy or deficits.

Problem-solving Identify and prioritize situational problems; plan and implement strategies
therapy to deal with top-priority problems.

Psychodynamic Use therapeutic relationship to maximize use of the healthiest defense

psychotherapy mechanisms and coping strategies.

• Problem solving and interpersonal psychotherapies are comparably efficacious.

• “New wave” cognitive-behavioral therapies (e.g., acceptance and commitment

therapy, mindfulness-based cognitive-behavioral therapy [CBT]) have demonstrated
efficacy in numerous studies. It is unclear as of yet whether new-wave versus
traditional behavioral therapies differ in mechanisms of action. Individuals not
responding adequately to traditional behavioral therapies may benefit.

• Growing evidence indicates that Internet-based CBT and brief therapy interventions
integrated into primary care to expand access to therapy are efficacious, with some
studies finding comparable efficacy to standard length interventions, but further

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research is needed.

• By 12 wk or earlier, psychotherapy and medication approaches are equally effective.

• Augmentation of standard depression treatment with CBT to address insomnia

(CBT-I) was found to significantly improve response rates.

• Official treatment guidelines recommend that medication be used as the first-line

treatment for patients with severe depression, although some studies have found
equal efficacy of medication and psychotherapy in the treatment of severe
depression.

• Evidence, although mixed, indicates that combined psychotherapy and medication

may be more effective than either treatment alone. Various types of evidence-based
psychotherapy or augmentation with psychotherapy, including CBT and
mindfulness-based behavioral therapy, appear to reduce the risk for future
recurrences compared to medication alone in some but not all studies, particularly
when medication is discontinued after symptomatic remission.

• Factors, including history of childhood maltreatment, presence of precipitant

stressful life events, family psychiatric history, the presence of anhedonia, and
depression severity, may affect treatment response and risk of recurrence. Numerous
genetic and neurobiologic variables that predict treatment response have been
identified, particularly in combination with one another or with clinical
characteristics. However, as of yet there are no universally accepted markers that can
aid clinicians in matching individuals to particular medications or interventions.

• Strict monitoring of patients who initiate antidepressant therapy is necessary both

for safety and to ensure optimal treatment. Use of self-report scales to measure
symptom severity is helpful in monitoring outcome and may result in improved
outcomes.

Pharmacologic Therapy 2
• Selective serotonin reuptake inhibitors (SSRIs) generally are first line. Approximately
30% achieve remission with the first prescribed medication after 3 mo of treatment.
Another 25% to 30% respond to treatment but do not achieve remission. Treatment-
refractory patients should be switched to another SSRI or to another class of

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medication, offered adjunctive medication such as bupropion, or referred for

evidence-based counseling. Approximately 25% more patients will achieve remission
with this secondary intervention.

• Response to antidepressants for many patients is seen as early as 2 wk, and among
patients showing little to no response, the odds of later response decrease the longer
patients remain unimproved. Conversely, rapid response to treatment predicted
improved outcomes in multiple studies.

• To date no benefit of combining antidepressants as first-line treatment. Also no clear

advantage has been identified for switching medications within vs. across different
classes, or to switching vs. augmentation. The Veterans Affairs (VA) Augmentation
and Switching Treatments for Improving Depression Outcomes (VAST-D) trial found
that switching to the antipsychotic aripiprazole resulted in statistically significant,
though modest, improvement in remission rates compared with switching or
augmenting with an antidepressant, although greater side effects resulted. 4

• Therapy should be continued for 4 to 9 mo after the full remission of symptoms.

• Electroconvulsive therapy is the most effective means available for the treatment of
severe, refractory depression. Transcranial magnetic stimulation (TMS) has also
shown evidence of efficacy though the magnitude of effects is more variable. To date
electroconvulsive therapy has shown superior efficacy; research is under way to
investigate mechanisms to increase the efficacy of TMS.

• Antipsychotic medication should be added for psychotic depression. Antipsychotic

medication has also been shown to be helpful in augmenting antidepressants for
nonpsychotic depression, and it may be beneficial for individuals with mixed
features, although more research is needed.

• Ketamine IV has been found to be rapidly effective in treatment-resistant and

suicidal depression. Recently intranasal esketamine (Spravato) has been approved for
use in treatment-resistant depression. Further research is needed to determine
whether positive effects are maintained, because effectiveness appears to fade
without repeated use. 5

Referral
• If treatment refractory

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• If patient suicidal or psychotic

• For suspected bipolar depression

Disposition
• Depression is often a relapsing and remitting illness.

• Physical symptoms may predict a favorable response to biologic intervention in

some but not all studies.

• Additional episodes experienced by >50% after one episode, with each additional
episode linked to increased risk for subsequent episodes.

• Without treatment, episodes last an average of 6 to 12 mo; risk of recurrence higher

without treatment. 2

• For many depressed individuals, subthreshold residual symptoms are present

between episodes and define the majority of an individual’s course of depression.
Such symptoms may lead to impairment and warrant prolonged treatment.

• Anxious distress, as defined by the DSM-5 specifier, was found in one recent study to
predict greater clinical severity and functional impairment, above and beyond
comorbid anxiety disorder diagnoses.

References
1. Zun L.S., Nordstrom K.: Mood disorders. Rosen’s emergency medicine: concepts and clinical
practice. 2018. Elsevier, Chapter 101Philadelphia pp. 1346-1352. e1.

2. Zimmerman M., D’Avanzato C.: Major depression. Ferri’s Clinical Advisor 2021. 2021.
Elsevier, Philadelphia

3. Burns R.B., et al.: Should this patient receive an antidepressant? Ann Int Med 2017; 167: pp.
192-199.

4. Mohamed S., et al.: Effect of antidepressant switching vs augmentation on remission among

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patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D
randomized clinical trial. J Am Med Assoc 2017; 318 (2): pp. 132-145.

5. Kim J., et al.: Esketamine for treatment-resistant depression—first FDA-approved

antidepressant in a new class. N Engl J Med 2019; 381: pp. 1-4.

Copyright © 2021 Elsevier, Inc. All rights reserved.

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